Not Applicable
Not Applicable
1. Field of the Invention
The invention generally relates to surgery and to a method and means for introducing or removing material from the body for therapeutic purpose. More specifically, the invention relates to apparatus and method in which electrical energy is applied to the body, such as by iontophoresis. Similarly, the invention may have application in a method and apparatus for surgery in which material is introduced into or removed from a body orifice or inserted or removed subcutaneously other than by diffusing through skin. The invention has application to a method of enhanced absorption of therapeutic material using iontophoretic treatment. A specific focus is blocking pain by precision administration of suitable treatment.
2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 1.98
Treatment of pain in humans is a topic of increasing research emphasis. One promising approach is by use of topical cocktails of ingredients for blocking pain from many origins. Rather than offering mere additive results, the multi-component cocktail of ingredients promises an unexpectedly high level of efficacy. Another developing approach is the use of improved delivery systems, which often can be used for the administration of treatments for diseases and conditions not solely limited to pain. Such delivery systems employ, gels creams, ointments, patches, bioadhesives, and iontophoresis that can deliver a variety of pharmaceuticals, alone or in combined administration. These approaches are exemplified in the following patents.
U.S. Pat. No. 5,900,249 to Smith discloses treatment of specific types and causes of pain by administration of a multi-component topical composition. For example, one component offers anesthetic pain relief that masks pain but does not correct the underlying cause. Another component reduces the sensation of pain by alleviating the physiological and neurotransmitter etiology of the pain. Each of the various active components functions differently in order to treat pain comprehensively, regardless of causes. Multiple components include, first, a vasodilating agent such as nifedipine; second, an antiinflammatory agent to reduce pain mediated by prostaglandins; third, a membrane stabilizing agent such as carbamazepine; and fourth, seratogenic and nonadrenergic reuptake inhibitor. These may be supplemented with a topical anesthetic and an anti-inflammatory steroid. These medications are delivered in a gel, ointment, or cream.
U.S. Pat. No. 5,837,289 to Grasela discloses a general purpose delivery system that employs transdermal delivery of medication in a patch. Iontophoresis is useful with the medication in the patch to increase skin permeation. A topical delivery system may use a cream carrying the desired medication plus penetration enhancers.
U.S. Pat. No. 6,210,394 Demopulos discloses a cocktail of pain blocking agents for topical administration by irrigating with combined inhibitors for both pain and inflammation. The treatment addresses pain caused by multiple distinct sources of pain, including prostaglandin, bradykinin, histamine, and serotonin. Each source can be inhibited by application of the corresponding receptor antagonists. The cocktail of anti-pain/anti-inflammation agents can be composed of fourteen classes of receptor antagonists and agonists, plus optional anti-spasm agents. An aspect of the treatment is a resulting synergy in certain combinations, believed to result from cross talk between various signaling pathways.
The practice of iontophoresis is useful to deliver a drug to a subject by driving charged ions of the drug through the skin of the subject by applying an electric potential. The effective component of the drug must carry a charge, and the electrical apparatus must be polarized in the proper direction to deliver the charged component. For example, a patch containing a drug with positive charge is applied to the skin of a subject. The patch is connected to the iontophoretic delivery system at the positive electrode. A negative electrode is connected elsewhere to the subject to complete a closed pathway for the electric current.
A recent and representative discussion of iontophoresis appears in U.S. Pat. No. 6,235,013 to Tapper. An iontophoretic patch and administration system employ alternating current of low frequency in order to avoid problems of skin damage and pH imbalance during administration.
Electrical probes can detect numerous topical points in the skin that show a dramatic drop in skin resistance, as measured in meg ohms. These points are neurodermal points and are identified as Langerhans complexes. They have a pattern in dermis tissues much like a grid. The presence of these neurodermal points has been known for a long time. In ancient China, equivalent points were known as points of Chi or energy, and in India they were called Prahna. In fact, they are a normal complex of afferent and efferent A delta sensory myelinated nerves, small unmyelinated xe2x80x9cC fibers,xe2x80x9d and tiny endocrine organelles. Such structures are capable of releasing NO, nitric oxide, and gamma amino butyric acid (GABA). They are also capable of locally releasing a variety of substances. These include Ca++ ions via the NMDA, aminocyclopentane-1,3-dicarboxylate (ACPD) receptors; substance P peptide; alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) receptors; and glutamate.
Persons born without Langerhans complexes in the superficial dermis cannot suffer pain. Thus, the pain process requires the projection of painful nociceptive afferents from superficial and deep structure onto the dermal grid of the Langerhans network. The afferent modulation at this level of preprocessing determines if there is painful perception at each dermatome with central projection of these neural holograms to ever-higher levels of modulation at the dorsal horn, substantia gelatinosa areas V to IX, rostrally to the thalamus and tectum of the midbrain and onto the cortical modulation. This process determines patterns of proprioceptive interpretation and, thus, muscle static and dynamic firing patterns. Spasm is modulated via red fiber tonic muscle fibers that cause spinal and joint subluxation, and further nociceptor stimulation via A delta afferent pain fibers and C fiber pain afferents. The earliest pattern on EMG is spectral imbalance in surface EMG with non-physiologic phase shifts in axial paraspinal muscle firing and increased greater than 400 Hz efferents to the spinal myotome or peripheral muscles.
A number of known electrical probes employ an electric current or resistance measurement to aid in administering drugs or performing a medical procedure. A representative example appears in U.S. Pat. No. 3,862,162 to Colyer, which combines a hypodermic needle with an electrical probe. The probe is useful to locate a nerve, which can be treated by injecting a selected medicament through the needle. U.S. Pat. No. 5,853,373 to Griffith et al. suggests the use of a similar needle and probe combination in order to locate a nerve for administration of anesthetic. U.S. Pat. No. 5,284,153 to Raymond et al. suggests using a nerve stimulator either to assist in administration of regional anesthesia or to guard against cutting specific nerves during surgery.
Thus, a technology is known for locating a nerve or neurodermal point by electrical detection, and this has aided in administering certain types of treatments or drugs. However, this technology has not been adapted to improve the efficiency or effectiveness iontophoresis. In particular, the method of this invention improves iontophoresis by first using a probe to locate a neurodermal point, and then placing a patch containing the drug over the located point, and driving the drug into the subject by applying an electrical current across the patch and the subject""s skin at the located point. The effectiveness of the treatment is improved, while the required quantity of drug often is substantially decreased. With a lower quantity of the drug required to be administered for effective treatment, the patient benefits by reduction in side effects. This results in an improved overall efficiency and effectiveness of treatment.
Further improvements in treatment are possible by selecting and formulating a polypharmaceutical preparation for application by topical means, which may include iontophoresis. The placement of an iontophoretic patch on a preselected neurodermal point, located by use of a probe, further improves the treatment.
An improved polypharmaceutical preparation can be formulated by the suitable selection and combination of an array of drugs. The preferred candidates include ketamine, which topically blocks the NMDA Ca++ channels. Gabapentin also is a glutamate antagonist. Carbamazepine is an AMPA (Na+ channel) receptor blocker, as is gabapentin. The 10-11 epoxide is the active molecule that modulates C fiber afferents at the Langerhans complex. Carbamazepine blocks peripheral sympathetic nerve receptors via the voltage-dependent sodium channels, in the same manner as it blocks these receptors in the dorsal root ganglion (DRG). Clonidine is an alpha 2 blocker that similarly blocks the alpha 2 receptor. Phenoxybenzamine is an alpha 1 agonist. It has much more power to block dorsal ganglionic afferents that synapse with the interneurons of the wide range neurons of areas V to IX of the dorsal horn, before ascending up Lissauer""s spinothalamic tract, carrying afferent painful stimuli to the thalamus. Nifedipine is useful for non-NMDA, voltage-sensitive calcium-channel blockade, which down regulates nitric oxide (NO) synthesis.
Pluronic lecithin organogel (PLO), topical vehicle allows the above pharmaceuticals to penetrate to the dermis and modulate up regulated activity in all these pathways that cause acute and chronic pain, modulation at the periphery.
There are three phases of rehabilitation: phase onexe2x80x94increased activity at the same pain level; phase twoxe2x80x94decreased pain at the same activity level; and phase three stabilizationxe2x80x94damping of the sine wave fluctuation status with less severe and frequent flare-ups in pain, spasm and deconditioning. Such topical pharmacotherapy has proven effective on numerous patients at accomplishing benefits at all three phases of rehabilitation. Static and dynamic spasm is reduced, and dynamic eccentric-concentric contraction is restored to proper in-phase 180-degree muscle firing for oppositional muscles across the paraspinal myotomes and peripheral muscles. Restoration of oxygenation, with prevention of vasoconstriction all improved tissue healing and reduced low oxygen tension dependant induction of fibroblast collagen III generation that with later remodeling will produce adhesions and neural entrapments. In other words, barriers to movement, vasoconstriction, and healing are removed via topical peripheral pharmacological blockade. The neural holographic image of the pain is blocked before it can be projected rostrally to the thalamus and cortex, with resultant muscle firing abnormalities, postural and dynamic changes and vasoconstrictive changes with subsequent deconditioning and development of atrophy.
There are estimated to be 50 million Americans with partial or total disability due to chronic pain. The world market is estimated to be about $7.7 billion for analgesics in US dollars. The American Pain Society estimates 45% of the population seeks medical help for persistent pain at some point. The cost to American workers and companies, including lost workdays and physician visits, is in excess of $100 billion per year in America, alone.
New scientific evaluation tools such as Quantitative Sensory Nerve Threshold Testing using the MediDx 7000 to map sensory nerve and sympathetic nervous function can add the dimension of quantitative assessment of the patient""s neuropathologic improvement or deterioration. Diagnostic spinal ultrasound (DSU) also will demonstrate improvements or deteriorations with changes to perineural edema and myofascial edema up to six inches on either side of the spinal cord sagittal plane, as well as changes in posterior element facet arthropathy. Application of these technologies can verify the efficacy as not only altering the patient""s reported pain and loss of function, but also the quantitative physiological parameters of improvement in A delta and C fiber physiology, as well as joint, muscle and soft tissue edema and inflammatory change.
Most pain has a strong neuropathic component. Current over-the-counter (OTC) preparations are not benign. Thus, safer approaches without systemic side effects are required. Delivery of these effective but toxic or sedating pharmaceuticals avoids systemic effects and is very useful, safer and gives an element of control and validation back to the sufferer. An effective topical preparation can significantly reduce reliance on OTC preparations and on more powerful, orally administered, centrally acting pharmacotherapies that carry with them significant risks and side effects. More rapid recovery and lower use of oral and injected drug therapies are obvious benefits, leading to more rapid reconditioning, and maintaining fitness for duty at work and fitness for recreation. Suppressing the image of pain in the peripheral Langerhans dermal complexes results in suppression of the primary pain image at its primary projection sites of the Langerhans complex network. Such a polymodal pharmcotherpeutic management plan will prove to be a key step in all forms of pain control in the 21st century.
It would be desirable to improve the efficiency of treatment using iontophoresis by locating effective treatment sites. In addition, it would be desirable to formulate and administer more effective treatments for pain syndromes, both by addressing multiple pathways of pain propagation and administering such treatment by improved methods.
To achieve the foregoing and other objects and in accordance with the purpose of the present invention, as embodied and broadly described herein, the method and apparatus of this invention may comprise the following.
A general object of the invention is to provide a new and improved composition and method of treatment of pain, utilizing topical preparations.
Another object is to provide a composition and method of the type described which provides the desired therapeutic response through topical administration in the form of cream-gel preparation, spray or aerosol, and topical iontophoresis methodology patch.
The invention provides a composition and method of treatment for alleviating pain. A solution of pharmaceuticals including phenoxybenzamine, ketamine, gabapentin, nifedipine, and carbamazepine in PLO carrier or other suitable topical preparation vehicle is applied topically to the painful region of the skin.
The invention is derived from research and observations showing local anesthetic blockade at the Langerhans complex network map of a pain-projected distribution. The mechanisms for pain modulation in the dermis provide a new theory of pain gate and prespinal cord modulation that can block afferent pain perception and the attendant reflex spasm, vasoconstriction, and atrophic and deconditioning effects that can result from a projected neural holographic image.
According to the invention, a method of administering a pharmaceutical agent suited for iontophoretic delivery to a human or animal subject is performed by, first, performing a point locating step by locating on a subject to be treated a preselected neurodermal point for receiving the pharmaceutical agent. Second, a patch application step is performed by applying to the subject, over the preselected neurodermal point, an iontophoretic patch containing the pharmaceutical agent to be administered. Third, a delivery step is performed by applying an electrical potential across the iontophoretic patch and the subject and delivering the pharmaceutical drug from the patch to the subject at the neurodermal point by iontophoresis.
According to another aspect of the invention, a polypharmaceutical composition for treating chronic pain by producing a blockade of the initiation and propagation of the pain stimulus in the Langerhans and other neuroendocrine vascular structures of the superficial and deep dermis is composed of, in combination, at least two pharmaceutical agents selected from the group consisting of an NMDA receptor blocker, a GABA receptor blocker, an AMPA receptor blocker, a nitric oxide synthase receptor blocker, a calcium channel blocker, an ACDP receptor blocker, a prostaglandin blocker, a leukotriene blocker, a substance P blocker, a bradykinin blocker, a neurotenin blocker, a peptide blocker, a TNF alpha blocker, a sympathetic alpha 1 receptor blocker, a sympathetic alpha 2 receptor blocker, and a non-NMDA calcium-channel blocker.
According to still another aspect of the invention, a method of treating pain by producing a blockade of the initiation and propagation of the pain stimulus in the Langerhans and other neuroendocrine vascular structures of the superficial and deep dermis, is performed through an administration step by topically administering to a person in need of such treatment an effective dosage of a combination of at least two pharmaceutical agents selected from the group consisting of an NMDA receptor blocker, a GABA receptor blocker, an AMPA receptor blocker, a nitric oxide synthase receptor blocker, a calcium channel blocker, an ACDP receptor blocker, a prostaglandin blocker, a leukotriene blocker, a substance P blocker, a bradykinin blocker, a neurotenin blocker, a peptide blocker, a TNF alpha blocker, a sympathetic alpha 1 receptor blocker, a sympathetic alpha 2 receptor blocker, and a non-NMDA calcium-channel blocker.
According to a further aspect of the invention, a method of treating pain in a human or animal subject by administering a combination of preselected effective pharmaceutical agents in an suitable dosage to treat a subject in need thereof, is carried out by, first, performing a point locating step by locating a predetermined neurodermal point associated with the pain. Second, the preselected pharmaceutical agents for treating pain are provided in a gel patch suited for delivery by electrically driving charged ions of the pharmaceutical agents from the path and into the subject. Third, an application step is performed by applying the provided gel patch to the predetermined neurodermal point on the subject. Fourth, a delivery step is performed by delivering the selected pharmaceutical agents from the patch to the subject by electrically driving charged ions of the pharmaceutical agents into the subject.
The accompanying drawings, which are incorporated in and forms a part of the specification illustrates preferred embodiments of the present invention, and together with the description, serves to explain the principles of the invention. In the drawings: